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BMC Cancer Jul 2021Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use...
BACKGROUND
Afatinib is one of the standard treatments for patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, data on the use of afatinib in patients with poor performance status (PS ≥ 2) are limited. This study aimed to retrospectively review the clinical outcomes and safety of afatinib treatment in EGFR-mutation-positive (EGFRm+) NSCLC patients with PS ≥ 2.
METHODS
The data for 62 patients who were treated at Linkou Chang Gung Memorial Hospital from January 2010 to August 2019 were retrospectively reviewed. Patients' clinicopathological features were obtained, and univariate and multivariate analyses were performed to identify possible prognostic factors. Data on adverse events were collected to evaluate general tolerance for afatinib therapy.
RESULTS
Until February 2020, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 58.1% (36/62), 69.4% (43/62), 8.8 months, and 12.9 months, respectively. The absence of liver metastasis (PFS: p = 0.044; OS: p = 0.061) and good disease control (p < 0.001 for PFS and OS) were independent favorable prognostic factors for PFS and OS. Bone metastasis (p = 0.036) and dose modification (reduction/interruption, p = 0.021) were predictors of disease control.
CONCLUSION
Afatinib demonstrated acceptable efficacy and safety in the current cohort. This study provided evidence to support the use of afatinib as a first-line treatment in EGFRm+ NSCLC patients with poor PS.
Topics: Afatinib; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Management; ErbB Receptors; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Treatment Outcome
PubMed: 34315431
DOI: 10.1186/s12885-021-08587-w -
Breast Cancer Research and Treatment Apr 2022Resistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family...
Afatinib alone and in combination with vinorelbine or paclitaxel, in patients with HER2-positive breast cancer who failed or progressed on prior trastuzumab and/or lapatinib (LUX-Breast 2): an open-label, multicenter, phase II trial.
PURPOSE
Resistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family blocker, afatinib, alone as first-line therapy in the advanced setting and in combination with vinorelbine or paclitaxel for those who progressed on afatinib monotherapy, in female patients with metastatic breast cancer who had failed or progressed on prior HER2-targeted therapy in the early disease setting.
METHODS
In this phase II, single-arm, two-part study (ClinicalTrials.gov: NCT01271725), patients in part A received afatinib 40 mg/day in 21-day cycles until disease progression or intolerable adverse events (AEs). Patients with progressive disease could then receive afatinib plus weekly vinorelbine 25 mg/m or paclitaxel 80 mg/m until disease progression or intolerable AEs (part B). The primary endpoint was confirmed objective response rate (RECIST v1.1).
RESULTS
Eighty-seven patients were enrolled and 74 were treated in part A (median age: 51 years [range 27-76]; 31 [42%] estrogen receptor-positive, 26 [35%] progesterone receptor-positive). Of these, 39 (53%) patients went on to receive afatinib plus vinorelbine (13 patients) or paclitaxel (26 patients) in part B. Thirteen (18%) and 12 (31%) patients achieved an objective response in parts A and B, respectively. The most common treatment-related AEs with afatinib monotherapy (any/grade ≥ 3) were diarrhea (68%/8%) and rash (49%/4%). Combination therapy was generally well tolerated, with no additive toxicity observed.
CONCLUSION
Afatinib treatment, alone or in combination with vinorelbine or paclitaxel, was associated with objective responses in ≥ 18% of patients with metastatic breast cancer for whom prior HER2-targeted therapy has failed. Treatment-related AEs were generally manageable, with few grade ≥ 3 AEs reported.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT01271725, registered 1 July 2011.
Topics: Adult; Afatinib; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lapatinib; Middle Aged; Paclitaxel; Quinazolines; Receptor, ErbB-2; Trastuzumab; Treatment Outcome; Vinorelbine
PubMed: 35138529
DOI: 10.1007/s10549-021-06449-4 -
Journal of Thoracic Oncology : Official... May 2020
Topics: Afatinib; Data Management; ErbB Receptors; Humans; Lung Neoplasms; Mutation
PubMed: 32340673
DOI: 10.1016/j.jtho.2020.02.013 -
Aging Jan 2024In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly...
Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.
BACKGROUND
In real-world practice, most patients with lung cancer are diagnosed when they are aged ≥65 years. However, clinical trials tend to lack data for the elderly population. Therefore, we aimed to describe the effectiveness and safety of afatinib, gefitinib, and erlotinib for elderly patients with epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC).
METHODS
Treatment-naïve patients with -mutated advanced NSCLC were enrolled at many hospitals in Taiwan. Patient characteristics and the effectiveness and safety of afatinib, gefitinib, and erlotinib were compared.
RESULTS
This study enrolled 1,343 treatment-naïve patients with -mutated advanced NSCLC, of whom 554 were aged <65 years, 383 were aged 65-74 years, 323 were aged 75-84 years, and 83 were aged ≥85 years. For elderly patients, afatinib was more effective, with a median progression-free survival (PFS) of 14.7 months and overall survival (OS) of 22.2 months, than gefitinib (9.9 months and 17.7 months, respectively) and erlotinib (10.8 months and 18.5 months, respectively; PFS: = 0.003; OS: = 0.026). However, grade ≥3 adverse events, including skin toxicities, paronychia, mucositis, and diarrhea, were more frequently experienced by patients receiving afatinib than those receiving gefitinib or erlotinib.
CONCLUSIONS
This large retrospective study provides real-world evidence of the effectiveness and safety of EGFR-TKIs for elderly patients with EGFR-mutated advanced NSCLC, a population that is often underrepresented in clinical trials and real-world evidence. Afatinib was more effective as a first-line treatment than gefitinib or erlotinib for elderly patients with -mutated advanced NSCLC.
Topics: Aged; Humans; Afatinib; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 38194721
DOI: 10.18632/aging.205395 -
Therapeutic Advances in Respiratory... 2018Epidermal growth factor receptor ( EGFR) gene mutations identify a molecularly defined subset of non-small cell lung cancer (NSCLC) patients who display an excellent... (Comparative Study)
Comparative Study Review
Epidermal growth factor receptor ( EGFR) gene mutations identify a molecularly defined subset of non-small cell lung cancer (NSCLC) patients who display an excellent sensitivity to EGFR tyrosine kinase inhibitors (TKIs). First-generation reversible EGFR TKIs, gefitinib and erlotinib have been proven to improve the objective response rate and to prolong the progression-free survival compared with standard chemotherapy in large phase III trials. Unfortunately, virtually all patients develop resistance to treatment, usually within 9-12 months. Afatinib is an irreversible ErbB family inhibitor initially designed to overcome the development of resistance. Compared with gefitinib in a first-line setting, afatinib prolonged progression-free survival and time to treatment failure, without impacting on overall survival in the general population of EGFR-mutant patients. However, afatinib has been shown to prolong overall survival in the subset of patients with an EGFR exon 19 deletion compared with chemotherapy. The aim of this review is to summarize the clinical evidence available to date and to critically discuss the place in therapy of afatinib in the rapidly expanding landscape of EGFR-mutant NSCLC first-line therapy.
Topics: Afatinib; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Survival Rate
PubMed: 30355049
DOI: 10.1177/1753466618808659 -
BMC Cancer Oct 2020Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. The molecular mechanisms of action for...
BACKGROUND
Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. The molecular mechanisms of action for anti-HER-family drugs in gastric cancer cells are incompletely understood. We compared the molecular effects of trastuzumab and the other HER-family targeting drugs cetuximab and afatinib on phosphoprotein and gene expression level to gain insights into the regulated pathways. Moreover, we intended to identify genes involved in phenotypic effects of anti-HER therapies.
METHODS
A time-resolved analysis of downstream intracellular kinases following EGF, cetuximab, trastuzumab and afatinib treatment was performed by Luminex analysis in the gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87. The changes in gene expression after treatment of the gastric cancer cell lines with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 h were analyzed by RNA sequencing. Significantly enriched pathways and gene ontology terms were identified by functional enrichment analysis. Furthermore, effects of trastuzumab and afatinib on cell motility and apoptosis were analyzed by time-lapse microscopy and western blot for cleaved caspase 3.
RESULTS
The Luminex analysis of kinase activity revealed no effects of trastuzumab, while alterations of AKT1, MAPK3, MEK1 and p70S6K1 activations were observed under cetuximab and afatinib treatment. On gene expression level, cetuximab mainly affected the signaling pathways, whereas afatinib had an effect on both signaling and cell cycle pathways. In contrast, trastuzumab had little effects on gene expression. Afatinib reduced average speed in MKN1 and MKN7 cells and induced apoptosis in NCI-N87 cells. Following treatment with afatinib, a list of 14 genes that might be involved in the decrease of cell motility and a list of 44 genes that might have a potential role in induction of apoptosis was suggested. The importance of one of these genes (HBEGF) as regulator of motility was confirmed by knockdown experiments.
CONCLUSIONS
Taken together, we described the different molecular effects of trastuzumab, cetuximab and afatinib on kinase activity and gene expression. The phenotypic changes following afatinib treatment were reflected by altered biological functions indicated by overrepresentation of gene ontology terms. The importance of identified genes for cell motility was validated in case of HBEGF.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Movement; Cell Proliferation; Cetuximab; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Phenotype; Phosphoproteins; Stomach Neoplasms; Trastuzumab; Tumor Cells, Cultured
PubMed: 33115415
DOI: 10.1186/s12885-020-07540-7 -
Future Oncology (London, England) Feb 2016In oncology, there is a clinical need for novel combination therapy regimens that maximize efficacy and delay resistance to individual treatment modalities. Given the... (Review)
Review
In oncology, there is a clinical need for novel combination therapy regimens that maximize efficacy and delay resistance to individual treatment modalities. Given the role of aberrant ErbB receptor signaling in the pathogenesis of many human cancers, there is rationale for incorporating afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, into such combinations. This review focuses on: pharmacological properties of afatinib that facilitate its use in combination; preclinical rationale for the combination of afatinib with other agents; and recently completed, and ongoing, clinical trials of afatinib-based combinations across tumor types. Based on these data, we emphasize a number of areas of high unmet medical need that could benefit from afatinib-based combinations, including patients with relapsed/refractory non-small-cell lung cancer.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Humans; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Quinazolines
PubMed: 26603212
DOI: 10.2217/fon.15.310 -
Asian Pacific Journal of Cancer... May 2021We aimed to evaluate the effectiveness and tolerability of Afatinib as first-line treatment of advanced epidermal growth factor receptor (EGFR) mutant non small cell...
BACKGROUND
We aimed to evaluate the effectiveness and tolerability of Afatinib as first-line treatment of advanced epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC) in a real-world setting.
PATIENTS AND METHODS
This is a retrospective study of Vietnamese patients with advanced EGFR-mutant NSCLC treated with first-line afatinib at the National Cancer Hospital from 1st January 2018 to 31st October 2020. Patients' demographic, clinical and treatment data were captured. Objective response rate (ORR), disease control rate (DCR), time to treatment failure (TTF) and tolerability were evaluated. We used Kaplan-Meier curve and log-rank test for survival, and Cox regression model for multivariate analysis.
RESULTS
A total of 44 patients were included. Common EGFR mutations (Del 19/L858R) were detected in 61% patients. Fifty percent of patients with uncommon mutations had compound mutations of G719X, L861Q and S768I. The ORR was 75% while DCR rate was 98%. The median TTF was 12.3 months (95% CI: 7.2-17.3); the mTTFs were 12.3 and 10.8 months for patients with common and uncommon mutations (p = 0.001), respectively, and 14.0 and 7.5 months for patients with Del 19 and L858R mutations (p = 0.067), respectively. Afatinib 30 mg once daily was the most common starting (77%) and maintenance (64%) doses. The mTTFs were 12.3 and 7.5 months for patients with 30 mg starting dose vs 40 mg dose (p = 0.256), respectively. Diarrhea, skin rash, paronychia and fatigue were observed in 32%, 30%, 25% and 9%, respectively. There was no grade 4 toxicity except three patients with grade 3 paronychia.
CONCLUSIONS
First-line afatinib is beneficial for Vietnamese patients with advanced EGFR-mutant NSCLC with a good response rate and prolonged TTF with manageable adverse event profile. Baseline brain metastasis status and starting doses do not significantly impact TTF.
.Topics: Adult; Afatinib; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Prognosis; Retrospective Studies; Survival Rate
PubMed: 34048189
DOI: 10.31557/APJCP.2021.22.5.1581 -
Clinical Lung Cancer Sep 2022Squamous cell carcinoma (SCC) of the lung has a markedly different molecular profile to adenocarcinoma of the lung and remains difficult to treat because of the lack of... (Review)
Review
Squamous cell carcinoma (SCC) of the lung has a markedly different molecular profile to adenocarcinoma of the lung and remains difficult to treat because of the lack of targeted therapies for this type of non-small cell lung cancer (NSCLC). With immune checkpoint inhibitors moving from second-line treatment to first-line in NSCLC, effective second-line options following immunotherapy is an urgent unmet need. Appropriate treatment decisions are currently hindered by a lack of prospective clinical data. However, available real-world data suggest that ramucirumab plus docetaxel warrants prospective evaluation in this setting. Also, afatinib is approved in the second line in patients with SCC progressing on first-line platinum-based chemotherapy and may also be an option following immunochemotherapy combinations. Afatinib has the advantage of oral administration with a well-defined tolerability profile. Docetaxel, gemcitabine and platinum-based chemotherapy may be options for some patients, but overall, there are very few options for patients requiring second-line treatment after immunotherapy. This lack of options has prompted efforts to further define the molecular profile of lung SCC to match patients with relevant targeted therapies and to elucidate additional genomic targets. In order to ensure patients with SCC of the lung receive optimal treatment, genomic testing is essential to identify those patients who might benefit from existing targeted agents or clinical trials, and further prospective data are urgently required to assess potential second-line regimens following immunotherapy.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Docetaxel; Humans; Lung; Lung Neoplasms; Platinum
PubMed: 35872084
DOI: 10.1016/j.cllc.2022.06.002 -
Clinical Journal of Oncology Nursing Oct 2018Afatinib is an oral, irreversible ErbB family blocker indicated for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with non-resistant... (Review)
Review
BACKGROUND
Afatinib is an oral, irreversible ErbB family blocker indicated for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in patients with non-resistant epidermal growth factor receptor (EGFR) mutations. Afatinib is also approved for the treatment of metastatic squamous NSCLC following progression on platinum-based chemotherapy. Common afatinib-associated toxicities include gastrointestinal and dermatologic events, which can be dose limiting.
OBJECTIVES
In this review, the authors describe clinical trial experiences with afatinib, as well as best practices and practical approaches to the management of afatinib-associated adverse events in EGFR mutation-positive NSCLC.
METHODS
Safety and tolerability data from phase 3 trials of afatinib were reviewed, together with real-life experiences from the authors' clinical practices.
FINDINGS
Patient education, combined with early assessment and effective management of afatinib-related adverse events as well as dose- reduction strategies, allows patients to continue treatment and maximize the clinical benefits of afatinib.
Topics: Adult; Afatinib; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Education, Nursing, Continuing; ErbB Receptors; Female; Humans; Male; Middle Aged; Mutation; Protein Kinase Inhibitors
PubMed: 30239509
DOI: 10.1188/18.CJON.542-548